Coagulation is a result of a complex system which controls the formation of matrix proteins. These matrix proteins, along with other elements such as platelets, form a barrier which is able stop the transport of vital body fluids, especially blood. Traumatic damage to the vasculature causing bleeding, is controlled by the coagulation system and a failure of this system can result in serious and life-threatening situations, such as hemophilia. However, there are many situations; when the coagulation system may be inappropriately activated resulting in a blockage of the flow of vital fluids, such as blood, and causing severe damage to the effected tissues. Some examples of pathologies related to inappropriate and pathological coagulation include pulmonary embolism, myocardial ischemia, myocardial infarction, cerebral thrombosis, stroke, local hypercoaguable caused by inflammation, syndromes related to disseminated intravascular coagulation, and the like. Thus, there is need for a constant balance and control of the coagulation system to maintain homeostasis and good health.
Fibrinogen is a 3.4 KD dimeric protein found in the blood circulation and in other fluids of the body. This protein is the source or reservoir of the protein fibrin. Fibrin is the main building block for the matrix which forms clots in the circulatory system.
In the coagulation system, fibrinogen is converted to soluble fibrin by the enzyme, thrombin. Thrombin production from its precursor, prothrombin, is controlled by a complex series of protein interactions which are known as the intrinsic and extrinsic coagulation systems. The soluble fibrin, produced by the action of thrombin on fibrinogen, is further converted in an insoluble form by the action of factor XIIIa. This resulting insoluble fibrin forms the matrix which along with other elements such as platelets, causes a clot or thrombus to form, thus stopping the flow of blood. (For further details on the coagulation system, see: "Goodman and Gilman's, The Pharmacologic Basis of Therapeutics", Eds. Gilman A. G., Goodman, L. S., and Gilman, A., 6th Ed., Macmillan Publishing Co., NYC, 1980, Chap. 58; "Harrison's Principles of Internal Medicine", Eds. Isselbacher, Adams, Braunwald, Petersdorf, and Wilson, 9th Ed.,McGraw-Hill Book Co. NYC, 1980, Chap. 54; and references cited therein).
Today, there are many therapeutic agents which are useful in controlling the coagulation system. Each of these agents, while often effective in preventing or treating inappropriate coagulation, have undesirable side-effects which limit their utility. Examples of agents which prevent coagulation include: 1) Heparin, a glycosaminoglycan polymer, blocks several of the coagulation factors resulting in a decreased conversion of prothrombin to thrombin. This agent must be given by injection and, being a heterogeneous mixture, control of its action is often difficult. 2) The coumarins and indan-1,3-diones, e.g., warfarin, dicumarol, phenindione, etc., affect the vitamin K dependent clotting factors. Although these agents are effective and orally available, they are often too effective in that great care must taken to limit potential uncontrolled bleeding, which may lead to an excess morbidity of mortality.
In addition, there are also agents which treat blood clots which have already formed, and agents which destroy unwanted clots as they form. These agents act by a different mechanism than those described, supra, these agents activate the conversion of plasminogen to plasmin, which in turn hydrolyze fibrin, thus dissolving the formed or forming clot. These agents are known as thrombolytic agents, and include streptokinase, urokinase, and plasminogen activator. These agents are very expensive and must be given by injection, thus limiting their utility for prevention.
Each of these agents suffers from the one common side-effect related to their mechanisms of action which limits their utility. The propensity to be too effective in either preventing clot formation or hydrolyzing those clots which are necessary, or, in other words, offering too narrow a therapeutic index, is a common problem all for these agents and presumably for others operating by similar mechanisms. Thus, most of the commonly used agents are contra-indicated in patients undergoing surgery, biopsy, CPR, or procedures involving the use of a catheter or with factors which dispose them to risk of hemorrhage. Such factors include ulcers, wounds, hypertension, infections, previous stroke, and the like.
The narrow therapeutic index of the known anti-coagulants and thrombolytics is problematic in common situations where a better controlled level of anti-coagulation would be useful. For example, surgeons often face a dilemma when a patient needs surgery, while also requiring anti-coagulant therapy. A patient suffering from cardiac ischemia may need by-pass surgery and clot formation would be necessary in the healing of the surgery, yet inappropriate clots may cause more ischemia and possible infarction.
Additionally, currently available agents pose potential problems when used to prevent inappropriate coagulation, ducts their propensity to become pathologically hypocoagulatory, and this makes them unpredictable and possibly dangerous in long term use.
For example, patients who are treated with current agents to prevent ischemia, such as cerebral stroke, are at risk of hemorrhage if they have a trauma such as a fall or break a bone.
Clearly, it would be of great value to medicine if an agent were available which would not block or destroy useful clotting, but rather lower the clotting threshold in order to lower the risk of inappropriate and pathological clotting.
Estrogen is known to lower the levels of fibrinogen in humans. It is also known that estrogen exerts a very significant protective effect on the cardiovascular system. There is considerable controversy as to the exact mechanism by which estrogen exerts its protective effects. Use of estrogen for the treatment of excess coagulation has not been thoroughly investigated due to its undesirable side-effects. These side effects are on the sex tissues in men or the threat of uterine or breast cancer in women. However, recent studies have shown a relationship between the use of estrogen in post-menopausal women and a reduction in myocardial infarction, an inappropriate coagulation sequelae. An agent which would have the ability to inhibit inappropriate coagulation such as estrogen, but without its side-effects, would have a great potential for use in human medicine.
In addition to fibrinogen's well documented role in the coagulation cascade, fibrinogen has been implicated as a factor in several other pathologies. Fibrinogen and fibrin are found in the synovial fluid of joints which are inflamed. Fibrinogen and fibrin have been associated with neoplastic metastasis. Decreasing fibrinogen levels in these conditions, without undo hypo-coagulation, may be useful.